These results indicate that the ACE DD genotype and its interaction with the PAI-1 4G4G genotype are independent risk factors for macroangiopathy, but not for the progression of diabetic nephropathy in NIDDM patients, and that the genotyping of PAI-1 and ACE polymorphisms, especially in patients with advanced diabetic nephropathy, may be useful for predicting and preventing macroangiopathy-related events.
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD), and as the disease progresses SHPT is associated with systemic consequences, termed CKD-mineral and bone disorder. Currently, cinacalcet is indicated for the treatment of SHPT; however, cinacalcet is associated with upper gastrointestinal adverse events. Evocalcet has been developed to address these issues, but the long-term safety and efficacy of evocalcet need to be evaluated. To more accurately reflect clinical practice, this phase 3, multicenter, open-label study was specifically designed without a cinacalcet washout period, and focused on those patients who switched from cinacalcet to evocalcet. A total of 137 SHPT patients undergoing hemodialysis were enrolled, of whom 113 switched from cinacalcet to evocalcet. The most frequent type of adverse drug reaction was decreased adjusted calcium. The incidence of gastrointestinal-related adverse events did not increase in a dose-dependent manner as the dose of evocalcet was increased. The percentage of patients achieving the target intact parathyroid hormone concentration increased from 40.9% to 72.3% with 52-week treatment. The corrected serum calcium and phosphorus levels remained largely unchanged throughout the study. The long-term safety and efficacy of evocalcet was confirmed using a clinically relevant intra-subject dose-adjustment strategy in SHPT patients undergoing hemodialysis.
Abeta2M (beta(2)-microglobulin-related) amyloidosis is a frequent and serious complication in patients on long-term dialysis. Partial unfolding of beta2-m (beta(2)-microglobulin) may be essential to its assembly into Abeta2M amyloid fibrils in vivo. Although SDS around the critical micelle concentration induces partial unfolding of beta2-m to an alpha-helix-containing aggregation-prone amyloidogenic conformer and subsequent amyloid fibril formation in vitro, the biological molecules with similar activity under near-physiological conditions are still unknown. The effect of various NEFAs (non-esterified fatty acids), which are representative anionic amphipathic compounds in the circulation, on the growth of Abeta2M amyloid fibrils at a neutral pH was examined using fluorescence spectroscopy with thioflavin T, CD spectroscopy, and electron microscopy. Physiologically relevant concentrations of laurate, myristate, oleate, linoleate, and mixtures of palmitate, stearate, oleate and linoleate, induced the growth of fibrils at a neutral pH by partially unfolding the compact structure of beta2-m to an aggregation-prone amyloidogenic conformer. In the presence of human serum albumin, these NEFAs also induced the growth of fibrils when their concentrations exceeded the binding capacity of albumin, indicating that the unbound NEFAs rather than albumin-bound NEFAs induce the fibril growth reaction in vitro. These results suggest the involvement of NEFAs in the development of Abeta2M amyloidosis, and in the pathogenesis of Abeta2M amyloidosis.
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